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MECHANISMS UNDERLYING NON-PHARMACOLOGICAL DEMENTIA PREVENTION STRATEGIES: A TRANSLATIONAL PERSPECTIVE

 

V. Alanko1,2, C. Udeh-Momoh1,3, M. Kivipelto1,3,4,5, A. Sandebring-Matton1,2,3,#

 

1. Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden; 2. Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden; 3. Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United Kingdom; 4. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; 5. Theme Inflammation and Aging, Karolinska University Hospital, Solna, Sweden

Corresponding Author: Anna Sandebring-Matton, Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden, anna.matton@ki.se, telephone +46-8-524 800 00, fax +46-8-31 11 01

J Prev Alz Dis 2022;
Published online January 11, 2022, http://dx.doi.org/10.14283/jpad.2022.9

 


Abstract

Since developing an effective treatment for Alzheimer’s disease (AD) has been encountered as a challenging task, attempts to prevent cognitive decline by lifestyle modifications have become increasingly appealing. Physical exercise, healthy diet, and cognitive training are all modifiable, non-pharmacological lifestyle factors considered to influence cognitive health. Implementing lifestyle modifications on animal models of AD and cognitive impairment may reveal underlying mechanisms of action by which healthy lifestyle contribute to brain health. In mice, different types of lifestyle interventions have been shown to improve cognitive abilities, alleviate AD-related pathology and neuroinflammation, restore mitochondrial function, and have a positive impact on neurogenesis and cell survival. Different proteins and pathways have been identified to mediate some of the responses, amongst them BDNF, Akt–GSK3β, JNK, and ROCK pathway. Although some important pathways have been identified as mediating improvements in brain health, more research is needed to confirm these mechanisms of action and to improve the understanding of their interplay. Moreover, multidomain lifestyle interventions targeting multiple risk factors simultaneously may be a promising avenue in future dementia prevention strategies. Therefore, future work is needed to better understand the synergistic impact of combinatory lifestyle strategies on cellular mechanisms and brain health.

Key words: Alzheimer’s disease, dementia, prevention, mouse models, multidomain, lifestyle.


 

Introduction

The high global prevalence of the leading neurodegenerative disease-causing dementia, Alzheimer’s disease (AD) has been linked to exponential increases in ageing populations world-wide (1), though trends of attenuated incidence in high-income countries have been observed (2). Due to the slow progress in AD-dementia drug development, dementia prevention has become increasingly important and has drawn significant attention during the past few decades. Recent reports have been disseminated in the last few years underpinning the possibilities and importance of considering lifestyle factors for dementia prevention (3). Livingston et al.’s seminal report (2020) suggested that as much as 40% of dementia risk is attributable to lifestyle factors (4). Around the same time, the World Health Organization published guidelines for lifestyle modification to reduce the risk of cognitive decline and dementia (5).
Dementia prevention has been investigated both by observational studies and randomized controlled trials (RCT), both with their respective benefits and limitations (6). Still, there is an incomplete understanding of the underlying mechanisms of action. Although brain changes and functions can be assessed during preventive interventions using neuroimaging techniques and fluid biomarkers, such methods will not reveal the complete mechanisms underlying the alterations. Identifying these mechanisms could result in new treatment strategies. To better understand probable underlying mechanisms, it is necessary to conduct prevention studies in pre-clinical AD models.
While several modifiable risk factors have been identified, in this review we will discuss the effects of lifestyle interventions rather than pharmacological strategies that may directly impact risk factors such as hypertension and diabetes. We consider physical exercise, diet, and cognitive training as the main preventive factors, as these may either directly or indirectly impact some of the other risk factors, including hypertension, obesity, and diabetes (7–9). We will further describe current evidence from non-pharmacological pre-clinical prevention studies in mouse models of mainly AD and ageing, and how they may be translated to clinical applications.

 

Physical exercise

AD-pathology, inflammation, and glial alterations

Extensive studies performed on dementia mouse models exposed to exercise training report positive outcomes in cognitive tests (10–18). Many of these studies report an increase of synaptic markers indicating preservation of synapses and their function in the brains of exercising mice (10–14, 19). Additionally, desired alterations in AD-related pathology after a period of exercise in AD transgenic mice have been observed in several studies (10–12, 15, 20). Physical training can induce the phosphorylated Akt/phosphorylated GSK3β system, which in turn may reduce tau pathology (11, 14). Exercise attenuates pro-inflammatory markers, microglia and astrocyte activation, and increases anti-inflammatory markers in mice; such changes have been observed in 3xTg-AD mice as a result of different exercise paradigms (11, 12, 21). In APP/PS1 mice, exercise reduced the count and intensity of plaque-associated astrocytes (20) while in physically active 5xFAD mice they were increased (13). The reduced neuroinflammation is suggested to be mediated via inhibition of the c-Jun N-terminal kinase (JNK) pathway (11) or activation of the microRNA miR-129–5p (16).
White matter is also affected early in AD progression (22). Total white matter volume decreases in mouse models of AD (17) but can be restored to the levels of wild type (WT) mice (17) or significantly increased compared to sedentary counterparts (23) with exercise. Decreased myelin in old WT mice can be improved by exercise (24), yet with conflicting results (25). Indeed, exercise seems to promote differentiation of oligodendrocyte progenitor cells and increase the number of mature oligodendrocytes in mice (26). Axon growth can be inhibited by myelin-associated factors via RhoA/Rho kinase (ROCK) pathway (24, 27), but also differentiation of oligodendrocytes is inhibited by the same pathway (28). Physical activity downregulates the ROCK pathway, which is suggested to mediate the increased myelination. Exercise further improves vasculature in the brain, particularly in the white matter, which otherwise is compromised in APP/PS1 mice (17).

Neurogenesis & anti-apoptotic pathways

One common finding in several pre-clinical studies is the increased levels of the brain-derived neurotrophic factor (BDNF) as a result of physical activity (10, 13, 14, 19, 29–31). BDNF expression is regulated to a great extent by other muscle-derived myokines, such as FNDC5 (fibronectin type III domain containing 5) and its cleavage product Irisin (32). FNDC5 expression is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (32). Expression of the mitochondrial biogenesis regulator PGC-1α may be induced by exercise (11, 12), although conflicting results have been reported (21). Furthermore, BDNF has a precursor form (proBDNF) and a mature form (hereafter referred to as BDNF), where proBDNF binds the receptor p75 and its co-receptor, Sortilin, activating for instance apoptotic signalling while BDNF mediates its effects via tropomyosin-related kinase B (TrkB) receptor signalling (33). Extracellular cleavage of proBDNF is executed by several different proteases into the mature form (34). There are at least two upstream regulators of BDNF processing, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), which process plasminogen to plasmin that in turn cleaves proBDNF to BDNF (35,36). Interestingly, tPA is activated by physical exercise (36). In the hippocampus, BDNF is a facilitator of long-term potentiation (LTP) and thus enhances memory and learning, neurogenesis, and synaptic plasticity. FNDC5/Irisin is involved in maintaining synaptic plasticity by stimulating BDNF expression, and levels of these proteins are reduced in the AD brain and CSF (18). When these are downregulated, LTP is impaired. The levels can, however, be restored by exercising, and thus memory can be improved or maintained (18). Additionally, exercise activates other neurotrophic factors involved in neurogenesis, as Kim and colleagues (12) did observe an increase in TrkB expression while BDNF levels were unchanged.
In 3xTg-AD mice, physical activity restored the levels of BrdU/NeuN-positive cells to the WT levels (12) or at least significantly increased compared to sedentary controls (14). In 5xFAD mice such effects have not been reported (13). An increase in newly formed neuronal precursors have also been shown in active WT mice (25, 37). Horowitz et al. (30) showed that not only was neurogenesis increased in exercising WT mice, but even in inactive aged mice when administered with plasma from the exercised mice. Similar results were reported when 3xTg-AD mice were administered plasma from young, exercised mice (19). This denotes that there is a clear axis between the training-induced systemic changes and the brain. Horowitz et al.’s study (30) specifically investigated the role of Gpld1 (glycosylphosphatidylinositol-specific phospholipase D1) and connected it to the increased BDNF levels and neurogenesis. The liver produces increased levels of Gpld1 in exercised mice, but also in physically active persons (30). However, the compound mainly remains in the periphery (30). Reflecting on the report, the effect on BDNF could be attributed to a Gpld1–uPA–plasminogen cascade. Finally, these effects were observed as an improved cognitive performance of the mice (19, 30).
Complementary to neurogenesis, exercise might also alleviate cell death in the brain (14, 15, 19, 24). This effect has been attributed to a decrease in pro-apoptotic markers like caspases, cytochrome c, and Bax, and additionally to an increase in anti-apoptotic markers like Bcl-2 (14, 15, 24, 31). Downregulation of the ROCK system is a plausible pathway reducing apoptosis (24), and as a downstream target of receptor p75 (38) the effect could be attributed either to a reduction in proBDNF or increase in BDNF. In exercised AD mice (14, 15) or in AD mice administered plasma from exercised mice (19) the levels of these different proteins are not necessarily restored to a WT level, but still significantly improved compared to sedentary mice. Intriguingly, resistance training did not affect Bax and Bcl-2 levels (11).

Metabolic factors & mitochondrial function

Glucose hypometabolism is a known feature of AD (39) and many mouse models with memory impairment demonstrate a deficiency in glucose uptake (10,40). Exercise can induce an increase in brain expression of glucose transporters GLUT1 and GLUT3 in APP/PS1 double-transgenic mice (10) as well as GLUT1 in NSE/APPswe mice (31). In addition to improved brain glucose homeostasis, physical activity improves peripheral glucose metabolism in 3xTg-AD mice (21). In accord-ance with improved glucose metabolism, exercise alleviated insulin resistance in high-fat-diet fed WT mice by activating insulin receptors substrate (IRS) and its downstream pathways PI3K–PDK-1–Akt–GSK3β (37).
An additional effect that physical activity appears to have on the brain is maintenance of mitochondrial function. Kim and colleagues (12) detected restoration of mitochondrial length and enhanced mitochondrial biogenesis in exercised AD mice. Likewise, in APP/PS1 mice, exercise recovered mitochondrial integrity and partly the ATP levels (10). When 3xTg-AD mice were administered with plasma from young, exercised mice, it resulted in a better capacity to maintain calcium homeostasis and in reduction of reactive oxygen species when compared to the other AD mice – yet the mitochondrial function was not returned to the WT levels (19). A similar effect was evident in 3xTg-AD mice undergoing treadmill exercise combined with light flickering (14). One possible mechanism of these effects could be the restoration of brain iron dyshomeostasis that contributes to oxidative stress (15).

 

Nutrition

Olive oils and polyphenols

There have been several attempts mimicking the Mediterranean diet (MeDi) in animal studies. As composing a full MeDi for mice is largely impossible, studies have investigated the effects of single nutrients or groups of nutrients that are thought to be the main health-promoting components of MeDi. Many of these nutrients are found in olive products and fish oils. Extra virgin olive oil-enriched diet improved working and spatial memory and increased synaptophysin expression in 3xTg-AD mice (41). Furthermore, both Aβ and tau pathology were diminished in the treatment group, active microglia alleviated, and autophagy seemed to be induced (41). In the APP mutant TgSwDI mice, Aβ pathology was ameliorated and some phosphorylated tau species were reduced by extra virgin olive oil consumption (42). The reduction of Aβ plaques and vascular depositions of Aβ was coupled to an increased clearance of the protein but even to a favourable APP processing pattern (42). Improved clearance was to some extent a result of increased expression of transporter proteins ApoE and ABCA1 (Apolipoprotein E and ATP-binding cassette transporter, respectively) (42).
Moreover, many studies have investigated the role of individual bioactive components of olive oil. Particular interest has been in studying the relationship between polyphenols found in olive oil and mitochondrial dysfunction and oxidative stress since polyphenols possess antioxidant activities (43). In APP/PS1 mice, hydroxytyrosol diet did not cause any major cognitive improvement nor did it affect Aβ pathology (44). Nonetheless, hydroxytyrosol reversed oxidative stress in the brains and restored mitochondrial protein levels, reduced the levels of the cleaved caspase 3, and alleviated neuroinflammation through inhibition of JNK pathway (44). Impacts on mitochondria have further been studied in aged NMRI mice fed with oleocanthal or ligstroside (45). Neither of the supplements affected the cognitive abilities of the mice, though those were not extensively studied. However, the life expectancy and cerebral ATP levels improved due to ligstroside diet, and a rationale that olive polyphenols improve mitochondrial respiration is supported by in vitro studies (45). In NMRI mice, a cocktail of purified secoiridoid polyphenols, including for example hydroxytyrosol, elevated ATP levels and moreover restored cognitive abilities (46). With oleuropein aglycone diet the AD mouse model TgCRND8 improved cognitive performance (47) as well as reduced Aβ load in different brain areas (47,48). The diet further induced autophagy and histone acetylation (47, 48).

Fish oils and Fortasyn Connect

Fortasyn Connect (FC) is a multi-nutrient supplement consisting of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), uridine monophosphate, choline, vitamins B12, B6, C, E, and folic acid, phospholipids, and selenium (49). FC diet has been shown to partly reverse cognitive deficits in APP/PS1 mice (50, 51). Yet, in another study with the same mouse model and diet, no such findings were reported (52), even though all three research settings have applied Morris Water Maze (MWM) tasks as the testing paradigm. ApoE4 and ApoE knock-out (KO) mice – models featuring the main genetic risk factor of sporadic AD – did not either improve learning nor memory in this particular cognitive test after FC diet (53). Although APP/PS1 mice improved learning after ingesting FC, the dietary impacts on Aβ burden, inflammation, and reactive oxygen species were very minor overall, as were the effects with fish oils or a combination of fish oils and plant sterols (50). However, when the dietary intervention was initiated at an earlier time-point (compare 3 months of age (54) versus 5 months of age (50)), even if the intervention was of shorter duration, the Aβ pathology was profoundly alleviated in the APP/PS1 mice (54). These results highlight the importance of early nutritional intervention for an impact on Aβ neuropathology. Moreover, while the FC diet seems to have a positive effect on the Aβ burden at an early stage of disease progression, this was not the case for a diet only enriched with DHA and uridine monophosphate, nor with either of them used alone (54).
Intriguingly, Jansen et al. (52) observed a significant increase in doublecortin-positive cells with the FC diet in APP/PS1 mice, indicating that the FC enhances neurogenesis. The level of these cells was restored to the WT level. On the contrary, a diet enriched only with DHA, EPA, and uridine monophosphate did not affect the number of doublecortin-positive cells (52), and the FC diet did not significantly increase the number of these cells in ApoE4 or ApoE KO mice (53). In APP/PS1 mice, the FC diet had also a positive impact on the degenerative burden of the cortex (54). Both of the diets did still result in a change in brain fatty acid composition, for example, by increasing the omega-3 to omega-6 ratio significantly and altering levels of brain oxysterols (52–54).

 

Environmental enrichment and cognitive training

Cognitive training

Cognitive training per se and its effects on cognitive abilities has not been extensively studied in mice – particularly in settings where the retention time is long, i.e. the time between training and testing. Nevertheless, the lack of research with long retention time was addressed in a recent study investigated APP/PS1 mice in different cognitive training set-ups (55). In the first setting (referred to as “trained”) mice were trained with MWM at the age of three months, and in the second setting (“overtrained”) at the age of two months and again at three months. Importantly, training was scheduled before or at the time of plaque formation. However, the study did not include control groups that would not receive training. In both set-ups, mice were tested at age of seven months with a similar setting as during the training periods, but with an additional six-day-long reversal task. At seven months, “trained” transgenic mice showed rescued memory, although there was a significant group difference compared to WT littermates that underwent the same training program. Such difference was not observed between the groups of “overtrained” mice. In further analyses, “overtrained” APP/PS1 mice performed overall at the same level as WT mice and better compared to “trained” APP/PS1 mice. No molecular nor cellular changes were assessed in the study.
In an earlier study, Tg2576 mice were trained with MWM (56). The researchers included non-training control groups, both transgenic and WT littermates. The day after the water maze tasks, mice were subjected to Contextual Fear Conditioning where trained mice performed significantly better than non-trained transgenic mice. Furthermore, training enhanced LTP and restored dendritic complexity in the hippocampus to a WT level. Training also increased levels of some postsynaptic proteins – an effect that was coupled to activation of calcium/calmodulin-dependent protein kinase II (CaMKII) – and ameliorated AD-related pathology.
A large-scale study by Billings et al. (57), investigated the effects of water maze training throughout the lifetime of 3xTg-AD mice, with training sessions once every three months beginning at the age of two months. Until approximately the age of 12 months, transgenic mice had a clear benefit of training and were performing at a WT level, yet at 15 months of age, this effect started to diminish. In addition to the learning and memory improvements, the harmful Aβ load was attenuated in 12-month-old trained mice, and tau phosphorylation was reduced possibly through reduced activity of GSK3β. Still, the favourable effects of cognitive training were most prominent when the training began before the emergence of neuropathology, although a later start of the training paradigm also improved the mice’s abilities. On the contrary, in another study, even if 16-month-old PDAPP mice demonstrated faster forgetting than WT counterparts already seven days post-training, their memory could be retrieved with a short retraining period at seven weeks after the initial training period (58).
MWM is, however, stressful for mice. Although the improved memory in both Tg2576 (56) and 3xTg-AD (57) mice can be attributed to the cognitive training, as the control groups exposed to swimming only did not perform on the same level during cognitive testing, stress is an important component affecting physiology and learning. Certain amount of stress enhances learning, yet highly stressed individuals may encounter an opposing effect (59). Future research should aim to implement less stressful cognitive training paradigms to measure a more accurate effect on cognitive performance.

Environmental enrichment

An alternative to cognitive training is utilising environmental enrichment as a cognitive stimulator in pre-clinical research (60). Environmental enrichment can compose of different factors and components, but generally, it includes larger cages compared to standard housing together with various objects, such as tunnels, ladders, nesting material, and items of different sizes and colours (60). These all contribute not only to enhanced cognitive stimulus but even to sensory and motor stimulations (60). Moreover, cages may also have running wheels and house a greater number of animals simultaneously. For this review, we want to separate the impacts of environmental enrichment and exercise, and therefore only studies implementing environmental enrichment paradigms excluding running wheels are discussed.
Independent of the time point of intervention start, enriched environment restored recognition memory in Tg2576 mice (61). However, spatial memory, as measured by MWM, was rescued only in those mice that lived in the enriched environment before the emergence of neuropathology. Enriched housing additionally counteracted the build-up of Aβ pathology in these mice. APP23 mice housed in an enriched environment have demonstrated improvements both in MWM and Novel Object Recognition (62). Moreover, environmental enrichment induced both hippocampal and cortical BDNF expression and reduction in Aβ plaque formation (62). On the contrary, in PDAPP-J20 mice that underwent enrichment intervention, a significant reduction in Aβ1–40 and Aβ1–42 peptides were observed, while the plaque load was unchanged (63). The volume of plaque-associated GFAP-positive astrocytes was also unaltered. Still, the volume of non-plaque-associated GFAP-positive cells was restored to a WT level due to environmental enrichment in these mice that otherwise have a significantly reduced number of astrocytes. Furthermore, the non-plaque-associated astrocytes in mice from enriched housing did not have as complex morphology as in standard housed mice.
Additionally, effects between exercise and environmental enrichment have been compared (64). In APP23 transgenic mice that were housed either in enriched cages or in a standard cages equipped with running wheels no effects on Aβ load were observed (64). Still, the mice living in an enriched environment demonstrated improved learning. Based on analysis of BrdU- and doublecortin-positive cells, hippocampal neurogenesis was not induced in either intervention group. However, a marker for a postmitotic phase, Calretinin, was increased in mice living in enriched cages. Levels of neurotrophin and BDNF expression were also increased in these mice compared to controls while such effects were not evident in the exercised mice.

 

Discussion & future directions

There is a high demand for strategies to cure and prevent dementia. Several of the herein discussed pre-clinical studies have reported clear benefits induced by singular lifestyle domain in mice (summarised in Fig. 1). When studying the effects in humans, some clinical trials investigating the effects from single-domain lifestyle changes have reported positive results, but likewise non-efficacious studies have been published (reviewed in 65).

Figure 1. Summary figure of intervention effects

The figure gives an overview of the the effects observed in lifestyle intervention paradigms in AD and WT mouse models. The light green arrows indicate an increase/amelioration in adjacent factors whereas the dark green arrows indicate a decrease/alleviation in adjacent factors. Abbreviations: Aβ, Amyloid beta; GLUT, glucose transporter; p-Tau, phosphorylated tau; WT, wild type.

 

Contradictions in efficacy between clinical and pre-clinical lifestyle intervention studies may be explainable by various considerations. First and foremost, mice are not men, and although there is great homology between brains, the significant inter-species differences in, for instance, cell types (66) may direct how the brain is influenced by various interventions. The issue is similar regarding biological homogeneity between mice with the same genetic background. In mice, it is near impossible to replicate the huge heterogeneity of different genetic and environmental risk factors present in humans. Considering AD, the transgenic mouse models developed for AD research replicate mainly familial AD instead of the more common sporadic AD. Thus, it is dubious to translate findings from these mice to sporadic AD. In attempts to translate findings, the great majority of drugs developed for AD have failed to reach their primary clinical outcomes (67). Additionally, mice lack the variation in living conditions experienced by humans. This results in mice adhering to the intervention naturally more stringently than humans. A factor that however remains to be explored is how the synergy of different lifestyle interventions affects the brain on a cellular and molecular level. Such questions could be investigated in mice exposed to multimodal lifestyle intervention strategies even if the discrepancies between mice and men are acknowledged.
Exercise seems to be the most studied lifestyle factor regarding molecular and cellular mechanisms in mice. Increased BDNF levels are likely to be one of the primary mediating players of different positive outcomes when exercising. BDNF impacts several downstream pathways, for example, reducing levels of Bax and boosting expression of Bcl-2 (as in (14)), thus promoting cell survival, inducing expression of glucose transporters (as in (10)), activating Akt for phosphorylation of GSK3β (68), hence suppressing tau phosphorylation, and mediating neurogenesis (30,37). Physical training promotes the expression of PGC-1α (11,12) and FNDC5/irisin (18) in the brain; factors that further contribute to the upregulation of BDNF expression. After translation, proBDNF can be further processed into mature BDNF. tPA levels increase due to exercise and hence increase the BDNF/proBDNF ratio (36). The exercise-induced BDNF levels could likely be attributed also to elevated liver-derived Gpld1 levels that in turn promote plasminogen processing through uPA (30). BDNF levels were mainly measured in exercise-related studies, but also a couple of studies report elevated brain BDNF levels as a result of environmental enrichment (62, 64).
GSK3β is considered to have a significant role in AD pathogenesis (69) and has been studied in several of the pre-clinical studies discussed in this review. Cognitive training (57) and physical exercise (11, 14, 37) have been found to increase the inactive, phosphorylated form of GSK3β and/or reduce the levels of the active form. These alterations have been accompanied by reductions in levels of its substrate phospho-tau (11, 14, 57). Nonetheless, even if infusion of plasma from young, exercised mice into AD mice had ameliorated several pathological features, it did not impact GSK3β activation and accordingly phospho-tau levels were also unchanged (19). Phosphorylation of GSK3β can be attributed to enhanced insulin signalling and activation of IRS (37).
Different lifestyle modifications furthermore have an impact on markers of neuroinflammation and oxidative stress. Microglia and astrocytes reduce in number, reactivity, and size or complexity (11, 12, 20, 41), but also some favourable alternations in cytokine levels have been observed (11, 21, 44). Some studies have shown that plaque-associated astrocytes decrease in number or complexity (20, 63), while others observe them as being more active around the plaques (13). The ameliorated neuroinflammation may be attributed to activation of the miR-129–5p (16) or inhibition of the JNK pathway and its down-stream targets (11, 44). Since JNK pathway is a down-stream target of receptor p75 (38), JNK pathway mediated reduction in neuroinflammation could be linked to changes in BDNF levels. A healthy lifestyle also maintains mitochondrial integrity and structure (10, 12), as well as mitochondrial function (10, 14, 45, 46). Regarding mitochondrial function, PGC-1α not only indirectly promotes BDNF expression (32), but serves as a marker of mitochondrial biogenesis (12).
To incorporate this multitude of beneficial mechanisms that promote brain health, multidomain interventions targeting several risk factors and mechanisms are likely to be the most beneficial approach, given the heterogeneity and multifactorial nature of AD (70, 71). Results from the pioneering multidomain lifestyle RCT – The Finnish Geriatric Intervention Study to Prevent Cog-nitive Impairment and Disability (FINGER) – supports the rationale for implementing multifactorial lifestyle changes, particularly in at-risk populations (72). Still, it should be mentioned that other multidomain lifestyle trials (e.g. preDIVA (Prevention of Dementia by Intensive Vascular Care) and MAPT (Multidomain Alzheimer Prevention Trial)) did not have measurable cognitive effects (73, 74).
Increased incidence of AD in global populations may be attributable to increased longevity, thus there is great need for promoting healthy ageing, especially in the context of brain health. The interventions reviewed here e.g. physical activity have also been shown to impact development of neuropathology, at least from studies in animal models. Further research is needed in earlier timepoints such as mid-life to evaluate the effect of lifestyle interventions on neurodegenerative brain changes in late-life. The diverse lifestyle-related interventions discussed in this paper have some clear benefits that are worth highlighting. First, they are all relatively easily available and do not necessarily require major financial input. Physical activity, a healthy diet, and cognitive challenges are further factors individuals may modify independently, in contrast to factors such as air pollution, traumatic head injury, and depression, which are all listed in Livingston et al.’s report as modifiable risk factors (4). Next, as encountered in the FINGER trial (72), the most common adverse event from such interventions is musculoskeletal pain. Thus, the disadvantages of healthy lifestyle changes are minor. Finally, an important aspect of such changes is the pervasive benefit of overall health. Not only was the CAIDE dementia risk score reduced (75), and cognitive functioning maintained or improved (72) in the FINGER trial, but additionally the risk of other chronic diseases and conditions related to lifestyle were diminished (76). Elucidating the mechanisms underpinning dementia prevention could yield precision medicine biomarkers and plausibly inform the discovery of novel therapeutic targets. Non-hypothesis-driven investigations to decipher the spectrum of mechanistic and cellular alterations in the brain as a result of lifestyle interventions could be a fruitful future avenue.

 

Funding: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.

Acknowledgments: This study was supported by the Swedish Research Council, Center for Innovative Medicine (CIMED) at Flemingsberg Campus, Stiftelsen Stockholms sjukhem, Sweden, Knut and Alice Wallenberg Foundation, Gun och Bertil Stohnes Stiftelse and Demensfonden.

Conflict of interest: The authors declare no disclosures.

Consent for publication: All authors have read the final version of the manuscript and have given their consent for publication.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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MULTIDOMAIN INTERVENTIONS TO PREVENT COGNITIVE IMPAIRMENT, ALZHEIMER’S DISEASE, AND DEMENTIA: FROM FINGER TO WORLD-WIDE FINGERS

 

A. Rosenberg1, F. Mangialasche2,3, T. Ngandu4, A. Solomon1,2, M. Kivipelto2,5,6,7,8

 

1.  Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 2. Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; 3. Aging Research Center, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden; 4. Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; 5. Theme Aging, Karolinska University Hospital, Stockholm, Sweden; 6. Stockholms Sjukhem, Research & Development Unit, Stockholm, Sweden; 7. The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, United Kingdom;
8. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

Corresponding Author: Miia Kivipelto,  Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Universitetssjukhuset, Karolinska Vägen 37 A, QA32, 171 64 Solna, Sweden, Phone: +46 (0)73 99 40 922, miia.kivipelto@ki.se

J Prev Alz Dis 2019;
Published online October 10, 2019, http://dx.doi.org/10.14283/jpad.2019.41

 


Abstract

Alzheimer’s disease (AD) and dementia are a global public health priority, and prevention has been highlighted as a pivotal component in managing the dementia epidemic. Modifiable risk factors of dementia and AD include lifestyle-related factors, vascular and metabolic disorders, and psychosocial factors. Randomized controlled clinical trials (RCTs) are needed to clarify whether modifying such factors can prevent or postpone cognitive impairment and dementia in older adults. Given the complex, multifactorial, and heterogeneous nature of late-onset AD and dementia, interventions targeting several risk factors and mechanisms simultaneously may be required for optimal preventive effects. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is the first large, long-term RCT to demonstrate that a multidomain lifestyle-based intervention ameliorating vascular and lifestyle-related risk factors can preserve cognitive functioning and reduce the risk of cognitive decline among older adults at increased risk of dementia. To investigate the multidomain intervention in other populations and diverse cultural and geographical settings, the World-Wide FINGERS (WW-FINGERS) network was recently launched (https://alz.org/wwfingers). Within this network, new FINGER-type trials with shared core methodology, but local culture and context-specific adaptations, will be conducted in several countries. The WW-FINGERS initiative facilitates international collaborations, provides a platform for testing multidomain strategies to prevent cognitive impairment and dementia, and aims at generating high-quality scientific evidence to support public health and clinical decision-making. Furthermore, the WW-FINGERS network can support the implementation of preventive strategies and translation of research findings into practice.

Key words: Alzheimer’s disease, cognitive impairment, dementia, multidomain, prevention, randomized controlled trial.


 

Dementia is the main cause of disability among older adults, affecting around 50 million people worldwide (1). Driven by population aging, this number is expected to increase rapidly to over 150 million by 2050, creating a major public health and social challenge (2). Alzheimer’s disease (AD) underlies the majority of dementia cases, often in association with vascular neuropathology. Disease-modifying therapies are not yet available for AD, and despite the recent positive signals in some of the ongoing randomized controlled trials (RCTs) testing anti-amyloid compounds, drug trials have mostly reported disappointing results (3,4). Given the evidence emerging from longitudinal observational studies, indicating that late-life cognitive impairment, AD, and dementia are heterogeneous and multifactorial conditions driven by a combination of genetic, vascular, metabolic, and lifestyle-related factors, the potential of dementia prevention through risk factor modification and management has gained increasing attention.
Findings from observational studies need to be substantiated by RCTs, which are considered the gold standard to verify the effect of an intervention. Results of the earlier, smaller, shorter-term prevention RCTs focusing on individual lifestyle components and risk factors have been mostly modest, and evidence from large, long-term trials is only beginning to emerge (5). Importantly, in light of the current knowledge about the complex and multifactorial etiology of late-onset AD and dementia, targeting several risk factors and mechanisms simultaneously, as well as tailoring interventions to individual risk profiles, may be necessary to obtain optimal preventive effects. So far, three large European multidomain lifestyle-based prevention trials have been completed: the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (6), the French Multidomain Alzheimer Preventive Trial (MAPT) (7), and the Dutch Prevention of Dementia by Intensive Vascular Care (PreDIVA) (8). The FINGER trial reported significant beneficial intervention effects on the primary outcome, namely change in global cognitive performance, among older ‘at risk’ adults from the general population (6). Notably, exploratory subgroup analyses of MAPT and PreDIVA also suggested cognitive benefits in subpopulations of participants with increased risk of dementia (7-9). Taken together, these studies indicate that administering multidomain lifestyle-based interventions to older at-risk adults may be feasible and effective. However, to fully understand the potential and impact of multidomain preventive interventions, their efficacy and feasibility needs to be explored in diverse populations and contexts worldwide. The FINGER model is now tested and adapted in several new preventive trials globally, and the World-Wide-FINGERS (WW-FINGERS) network (https://alz.org/wwfingers) was launched to support these joint initiatives aiming to reduce the burden of cognitive impairment and dementia. This article will provide an up-to-date overview of the multidomain intervention concept, lessons learned from the recent multidomain RCTs, and future directions in the field.

 

Modifiable risk and protective factors of cognitive impairment, Alzheimer’s disease, and dementia: a window of opportunity for prevention

Increasing evidence from long-term prospective cohort studies linking several modifiable risk and protective factors with late-onset dementia and AD has accumulated during the past decades (10, 11). These include vascular and metabolic risk factors and disorders, lifestyle-related, and psychosocial factors. It is also common that neurodegenerative and vascular pathology co-occur, particularly in older adults with dementia, and mixed dementia has been reported to be the most common type of dementia among individuals older than 80 years (12, 13). With regard to several vascular risk factors, the association with dementia risk is modified by age, and different risk factors may be relevant at different time points in life (14). For example, hypertension, obesity, and hypercholesterolemia in mid-life are risk factors for late-onset dementia and AD (15), but the opposite association has been reported later in life and in studies with shorter follow-up times, possibly reflecting reverse-causality (i.e., those factors decrease in the early, asymptomatic stages of dementia most likely as a consequence of the disease) (16, 17). In addition to vascular and metabolic factors (high blood pressure and cholesterol, obesity, diabetes, impaired glucose metabolism), smoking (18), excessive use of alcohol (19), depression (20), as well as other psychosocial factors, such as work-related stress, feelings of hopelessness or loneliness, and infrequent social contacts (21-23), are associated with an increased dementia risk. Protective factors for cognitive impairment, dementia and AD include regular physical activity (24), having a higher formal education (25) and an intellectually demanding and stimulating work (occupational complexity) (26), as well as engaging in cognitively and mentally stimulating leisure activities (27). Social engagement and having a rich social network have also been associated with a reduced risk of dementia and AD (28, 29).
Among pharmacological treatments, both observational studies and RCTs have indicated that antihypertensive drugs may be associated with a reduced risk of AD and dementia (30). The recent large, long-term Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition IN Decreased Hypertension (MIND) RCT reported that intensive blood pressure control (goal <120 mmHg) can be more effective in reducing the risk of cognitive impairment than standard blood pressure control (goal <140 mmHg), although the question of the optimal therapeutic target for systolic blood pressure among oldest old individuals (85+ years) still remains (31). Findings regarding other medications, such as statins, hormone replacement therapy, and non-steroidal anti-inflammatory drugs, are conflicting, as the beneficial effects suggested by observational studies have not been confirmed in RCTs (10).
In relation to diet, some individual nutrients, including omega-3 polyunsaturated fatty acids, vitamins B6 and B12, folate, vitamin D, and vitamins A, C, E (antioxidants), have been associated with a reduced risk of dementia in observational studies (32), although no conclusive evidence has so far emerged from trials testing nutraceutical supplements. Furthermore, regular intake of fish, fruits, vegetables, and nuts have been linked with a reduced risk of cognitive impairment and dementia. Among dietary patterns, cognitive benefits have been reported for different diets which are based on frequent consumption of fruits and vegetables, unsaturated fats, whole grain products, and fish: the Mediterranean Diet, the DASH (Dietary Approaches to Stop Hypertension), the hybrid MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, and the healthy Nordic diet (33-37). As opposed to single nutrients, the role of healthy and balanced dietary patterns may be more relevant, because nutrients have cumulative and synergistic effects.
Overall, it has been estimated that approximately 35% of dementia cases worldwide could be attributable to nine modifiable risk factors: low educational attainment in early life, midlife hypertension and obesity, diabetes mellitus, smoking, physical inactivity, depression, social isolation and hearing loss over the entire adult life course (38). This indicates clearly a prevention potential across the lifespan. In line with these findings, secular trend studies have indicated that the age-specific incidence and prevalence of dementia may have declined in some Western countries (39), potentially as a result of improved treatment of cardiovascular disease and vascular risk factors, reduction in smoking, increased educational attainment, and an overall improvement in lifestyle. However, the prevalence of dementia has been shown to increase faster than expected in countries like China and Japan (40,41), and with increasing prevalence of some risk factors, such as obesity and type 2 diabetes (42), there is a great need for global efforts to manage risk factors and reduce the burden of dementia.
A key issue to consider in preventive interventions is the fact that multiple risk and protective factors for dementia and AD usually co-occur and interact across the lifespan to determine the individual’s overall risk of dementia. For instance, in the context of interactions between genetic and environmental factors, it has been reported that the harmful effects of unhealthy lifestyle (i.e., unhealthy diet, alcohol misuse, smoking, physical inactivity) may be more pronounced among carriers of apolipoprotein E (APOE) ε4 allele, which is the most well-known genetic risk factor of late-onset AD (43). Furthermore, vascular factors can have additive effects (10). Overall, co-occurrence of risk factors, as well as their time- and age-dependent effects, underline the complexity of dementia prevention and imply that a ”one-size-fits-all” preventive approach might not be effective. Instead, a tailored, life-course approach targeting multiple risk factors is likely needed for effective prevention of cognitive impairment and dementia. This means that middle-aged and older adults, as well as individuals with heterogeneous risk profiles, may benefit from somewhat different multidomain preventive strategies in order to change their risk profiles.

 

From observational studies to clinical trials: large multidomain lifestyle-based interventions

Three pioneering, large, long-term multidomain lifestyle prevention trials have been recently conducted in Europe: the Finnish FINGER trial; the French MAPT trial, and the Dutch PreDIVA trial.
The two-year FINGER trial (NCT01041989) is the first large, long-term, multicenter RCT showing  a significant effect of the multidomain lifestyle intervention against cognitive decline among older adults who had increased risk of dementia (6, 44). The FINGER trial enrolled 1260 older adults aged 60-77 years, recruited from previous population-based surveys. Inclusion criteria were as follows: increased risk of dementia based on the CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score (≥6 points) (45); and cognitive performance at the mean level or slightly lower than expected for age. Participants were randomized into the multidomain intervention or control group. The multidomain intervention was delivered by trained professionals through both individual sessions and group activities, and it consisted of dietary counseling, exercise, cognitive training, social activities, and monitoring and management of vascular and metabolic risk factors. The control group was offered regular health advice.
The primary outcome of the trial was change in cognitive performance measured by a neuropsychological test battery (NTB) composite score, and secondary cognitive outcomes included domain-specific NTB scores. After two years, the intervention showed significant beneficial effects on the NTB composite score (25% more improvement compared to control), as well as on executive functioning (83% more improvement), processing speed (150% more improvement), and complex memory tasks (40% more improvement). Furthermore, the intervention group had a lower risk of cognitive decline. Follow-ups at 5 and 7 years have been recently completed to determine long-term effects (data analysis is ongoing). The multidomain intervention was safe and well accepted, with high adherence and a low drop-out rate (12%), supporting the feasibility of lifestyle interventions in older at-risk adults. Importantly, the intervention benefits were not limited to cognition: additional favorable effects included body mass index (BMI) reduction (6), improved adherence to dietary guidelines and recommendations (46), and increase in physical activity (6) and health-related quality of life (47). The intervention also improved physical performance and supported daily functioning (48) and lowered the risk of multimorbidity as well as risk of developing new chronic diseases (49). Notably, pre-specified subgroup analyses indicated that the intervention was beneficial regardless of age, sex, education, vascular risk profile and baseline cognitive performance, indicating that the beneficial effects were not limited to a subset of participants, but findings may be generalized to a large population of older adults at increased risk of dementia (50). APOE ε4 carriers got clear benefit from the intervention (51).
The three-year MAPT trial (NCT00672685) is a large, long-term RCT combining lifestyle-based intervention with a nutraceutical compound (7). MAPT enrolled 1680 community dwellers aged 70 years or older who had either subjective memory complaints, limitation in one instrumental activity of daily living, or slow gait speed. In the four parallel arms of the RCT, two intervention groups received a multidomain lifestyle intervention consisting of cognitive training and counseling on nutrition and physical activity, either alone or in combination with omega-3 fatty acid supplementation. One intervention group received only the omega-3 fatty acid supplementation, and one arm was assigned to placebo. The primary outcome was change in a cognitive composite score, and secondary outcomes included the individual components of the composite score, other cognitive test scores (e.g. Mini-Mental State Examination MMSE), and the Short Physical Performance Battery and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Prevention Instrument scores. Although the trial failed to meet its primary outcome, beneficial intervention effects were observed when both groups receiving the multidomain lifestyle intervention were combined. Also, the combined multidomain lifestyle plus omega-3 fatty acid intervention had beneficial effects on some secondary outcomes (ten MMSE orientation items). Moreover, exploratory analyses indicated beneficial effects in specific subgroups of at-risk participants: those with brain amyloid pathology or a CAIDE risk score of ≥6 points (7, 9), which was the same cut-off used in FINGER to select participants.
The PreDIVA (ISRCTN29711771) is a six-year study targeting 3526 older adults aged 70-78 years, recruited via general practices (8). Compared to the FINGER and MAPT participants, the PreDIVA population was rather unselected. The intervention group received a nurse-led multidomain intervention consisting of advice concerning healthy lifestyle and intensive vascular care and risk factor management, including initiation or optimization of antithrombotics and pharmacological treatments for hypertension, dyslipidemia, or diabetes, when necessary. The control group was offered regular care. The main results of the trial did not show any difference in dementia incidence, which was the primary outcome, between the intervention and control groups. However, in the exploratory analyses, a reduction in the incidence of dementia was observed among individuals with untreated hypertension who adhered to the treatment during the trial.
Several important lessons can be learned from these large multidomain prevention trials. First, selecting the right target population at the right time is crucial. Targeting at-risk individuals (as opposed to an unselected population) is likely the most feasible strategy. Second, the FINGER trial demonstrated the importance of starting early enough: the prevention potential of a multidomain lifestyle intervention, especially if not combined with pharmacological treatments, may be highest among relatively healthy and younger old adults. Finally, the content of the intervention is crucial. The intervention may need to be intensive enough and preferably include also active counseling and coaching delivered in different ways (not only advice). Based on the content and duration of the intervention sessions and study visits, the FINGER intervention was the most intensive, and the participants attended both group and individual sessions. Despite the relatively intensive nature of the intervention, adherence was high, as approximately 72% of the participants reported at least some engagement in all intervention components. Thus, the FINGER multidomain intervention seemed feasible, pragmatic, and not too strenuous. Designing and adapting the content of the intervention for various target populations is essential to optimize the effect. Finally, the choice of an appropriate outcome measure to assess intervention effects is also important. Incidence of dementia is a robust outcome, and trials with such outcome would require a large sample size and long-term follow-up, especially when targeting cognitively healthy older adults. For this population, there is currently no gold standard measure to detect cognitive changes predictive of future dementia. However, composite cognitive scores capturing several cognitive domains may be useful (52), not only to detect early changes typical for AD, but also for vascular cognitive impairment, since both disorders often co-occur in advanced age.

 

Other innovative multidomain preventive strategies

Building upon the experiences of the preventive RCTs conducted so far, the next generation of multidomain prevention trials has started to incorporate and utilize novel technologies and tools, such as eHealth and mHealth, to optimize the delivery of multidomain interventions. One example of an Internet-based eHealth study is the Healthy Aging Through Internet Counselling in the Elderly (HATICE, ISRCTN48151589), which is a European 18-month RCT testing the efficacy of an Internet platform in improving self-management of cardiovascular risk factors for prevention of cardiovascular disease and cognitive decline (53). The trial enrolled 2724 non-demented, computer literate community-dwellers aged 65+ from Finland, France, and the Netherlands. Participants were required to have at least two cardiovascular risk factors and/or history of cardiovascular disease or diabetes. Participants were randomized 1:1 to intervention and control groups. The intervention group had access to an interactive Internet platform, designed to encourage lifestyle changes with the remote support of a lifestyle coach, according to national and European guidelines for cardiovascular risk factor management (54). The control platform included only basic health information and no interactive features or coach support. The trial has been completed, and data analysis is ongoing. If the delivery of preventive interventions through Internet or e.g. via mobile applications proved to be feasible and effective and induced sustained behavioral changes, it could support self-management and be a cost-effective way to reach and involve a large population across the world.
While the FINGER, MAPT, and PreDIVA trials targeted older adults from the general population, some new multidomain prevention studies focus on at-risk populations in clinical settings. One particularly relevant target population for multidomain prevention are individuals with prodromal AD. For this more advanced and symptomatic state of AD dementia risk, lifestyle and vascular changes alone may not be sufficient. Rather, a combination of lifestyle and pharmacological approaches may be necessary to prevent or delay the onset of dementia. There are currently no proven therapeutic options available for such individuals, but in the multinational European LipiDiDiet trial (NTR1705) (55), the effects of the medical food product Fortasyn Connect (Souvenaid) were investigated in 311 memory clinic patients with prodromal AD, as defined by the International Working Group (IWG)-1 research criteria (56). Fortasyn Connect is a mixture of multiple nutrients, such as vitamins, polyunsaturated fatty acids, and phospholipids, which improves the formation and function of synapses (57). The primary outcome of the LipiDiDiet trial was change in cognitive performance measured with an NTB composite score. Secondary outcomes included change in e.g. memory scores, Clinical Dementia Rating-Sum of Boxes (CDR-SB), and brain volume. The two-year core trial was completed in 2015. Despite no significant effect on the primary outcome, group differences in favor of the treatment group were observed for cognitive and functional outcomes (45% less worsening in the CDR-SB in the intervention group), and hippocampal atrophy (26% less deterioration in the intervention group) (55). Notably, the observed decline in the NTB in the control group was smaller than expected. Analyses of the intervention effects at 36 months will be completed soon.

Going global: from FINGER to World-Wide FINGERS

Following the encouraging results of the FINGER trial, the World-Wide FINGERS (WW-FINGERS, https://alz.org/wwfingers) network was launched in July 2017 in connection to the Alzheimer’s Association International Conference in London (founder and scientific lead: Professor Miia Kivipelto; hosted by Alzheimer Association). By collectively convening international research teams under the WW-FINGERS leadership of Prof. Miia Kivipelto and Dr. Maria Carrillo, WW-FINGERS will facilitate data sharing and joint analysis across studies, establish opportunities for joint initiatives across country borders, and strengthen the potential evidence-base for multidomain lifestyle interventions.
This initiative supports and coordinates other trials worldwide in testing the feasibility and efficacy of FINGER-type preventive interventions in different at-risk populations, across diverse geographical and cultural settings. All WW-FINGERS trials share the same key concept of a pragmatic multidomain approach, i.e. targeting several modifiable risk factors simultaneously. WW-FINGERS will facilitate data sharing and joint analysis across studies, and to ensure comparability of the results and to facilitate pooling of accumulating data, the trials aim to use common core outcome measures. At the same time, local and cultural adaptations will be applied in relation to the content and delivery method of the intervention. For example, dietary counseling will follow national recommendations while taking into account country- or region-specific habits, and pharmacological vascular risk factor management, when applicable, will be based on national care guidelines. This is essential to improve engagement and adherence, and subsequently, to facilitate the effective and sustainable implementation of preventive strategies. Several countries worldwide have joined the WW-FINGERS network and are currently at different stages of planning and conducting their FINGER-type prevention trials (Figure 1). Recruitment is already ongoing in several trials.

Figure 1. World map with countries which are involved in the WW-FINGERS network. Blue indicates involvement in ongoing WW-FINGERS studies. Studies are currently planned in countries marked with purple

Figure 1. World map with countries which are involved in the WW-FINGERS network. Blue indicates involvement in ongoing WW-FINGERS studies. Studies are currently planned in countries marked with purple

 

WW-FINGERS trials

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), supported by the Alzheimer’s Association, aims to test the FINGER intervention in a more diverse US population. It is a two-year trial targeting 2000 older adults aged 60-79 years with normal cognition but increased risk for future cognitive decline. The trial will compare two lifestyle-based interventions (structured vs self-guided lifestyle intervention), which vary in their intensity and structure. Another ongoing trial testing the FINGER-based model is the randomized controlled Multimodal INtervention to delay Dementia and disability in rural China (MIND-CHINA), aiming at recruiting up to 3500 older adults aged 60-79 years who are living in rural areas of the Shandong province. The MIND-CHINA trial uses cluster randomization by village and includes two intervention arms and a control arm. Due to high prevalence of untreated vascular risk factors in this population, the trial will focus on the management and treatment of these factors. Participants in the vascular intervention group will be provided with pharmacological control and management of three major vascular risk factors (hypertension, dyslipidemia, diabetes); the multidomain intervention group will have both the management of the vascular risk factors and a multidomain lifestyle intervention. In the lifestyle intervention, special emphasis will be placed on reducing salt intake, which is a key dietary challenge in China. In Singapore, the six-month feasibility study SINGapore GERiatric intervention study to reduce physical frailty and cognitive decline (SINGER) targeting 70 participants with mild/moderate frailty and/or cognitive impairment is ongoing. The two-year study AUstralian-Multidomain Approach to Reduce Dementia Risk by PrOtecting Brain Health with Lifestyle intervention (AU-ARROW) is currently planned in Australia. Another Australian multidomain prevention trial, the ongoing three-year Maintain Your Brain (MYB) trial, is associated with WW-FINGERS (study design and outcomes not fully harmonized with other WW-FINGERS studies). The MYB RCT randomized 6236 non-demented community-dwellers aged 55-77 years. Assessments and interventions are conducted online, and the multidomain eHealth intervention consists of exercise, cognitive training, dietary advice, guidance to stop smoking and reduce alcohol consumption, blood pressure and cholesterol management, and cognitive behavior therapy to manage depressive symptoms and to facilitate social interaction.
Another initiative within the WW-FINGERS network is the multinational European collaboration project MIND-AD – Multimodal preventive trials for Alzheimer’s Disease: towards multinational strategies, which is based on the promising results of the FINGER and LipiDiDiet trials. In the ongoing six-month Multimodal Preventive Trial for Alzheimer’s Disease (MIND-ADmini)(NCT03249688) pilot trial (extended six-month follow-up in some countries), a multidomain lifestyle intervention derived from the FINGER trial is tested both alone and in combination with Souvenaid among individuals with prodromal AD and vascular or lifestyle-related risk factors. The control group receives usual care and regular health advice. Trial participants were recruited from Finland, France, Germany, and Sweden, and the main objective is to assess the feasibility of the multidomain intervention in this population. MIND-AD can serve as a model and platform for future trials combining non-pharmacological and pharmacological approaches to prevent or delay the onset of dementia. A master protocol for combination therapy is currently under development.
In addition to the abovementioned trials, WW-FINGERS interventions are also planned in several other countries including Japan, Canada, UK, the Netherlands, Spain, Italy, India, South Korea, Malaysia, and several Latin American countries (LATAM FINGER project) (Figure 1).

 

Conclusions

Prevention has been recognized as pivotal in halting the expected worldwide increase of AD and dementia cases. Successful preventive approaches should be feasible, accessible, cost-effective, and sustainable for populations in different geographical, economic, and cultural settings. Several modifiable risk factors, which can be managed to promote brain health and reduce the risk of late-life AD and dementia, have been identified. Yet, the majority of the observational studies on risk and protective factors have been conducted in high-income countries, with few findings available from low- and middle-income countries, which are facing the highest rise in dementia prevalence and incidence. In fact, by 2050, 68 % of all people with dementia worldwide are expected to live in low- and middle-income countries (1). The World Health Organization has invited experts worldwide to produce a global action plan and guidelines for cognitive decline and dementia risk reduction (58), and studies documenting prevalence and time-trends of risk factors in low- and middle-income countries can help develop preventive models for these areas.
The multidomain preventive approach has already proven its efficacy in other age-related chronic conditions (diabetes mellitus, cardiovascular disease (59,60)), and can facilitate also the reduction of dementia risk by addressing the multifactorial, complex, and heterogeneous nature of late-life cognitive impairment, AD, and dementia. Importantly, it offers prevention potential on a large scale, with possibilities for worldwide implementation. Country-specific adaptations will be crucial to ensure effective implementation of multidomain preventive interventions in different cultural, geographical, and economical settings, as well as public health care systems. Introduction of innovative eHealth and mHealth tools can facilitate implementation and monitoring of the interventions, while reducing costs and reaching larger regions and populations. The proportion of older adults using Internet is increasing, supporting the use of eHealth-based approaches, but feasibility is a key issue and is actively investigated. For instance, in the HATICE RCT older adults were involved in the development of the Internet platform that was used to deliver the multidomain intervention, in order to optimize its acceptability and use (61). Similar efforts may be needed also in future trials investigating eHealth or mHealth tools.
The complex nature of late-life cognitive impairment, AD, and dementia translates into a need to identify different risk profiles in order to develop tailored preventive strategies, within the framework of preventive precision medicine. WW-FINGERS is a landmark initiative, which will facilitate identification of efficacious preventive approaches for specific risk profiles and cost-effective implementation of such approaches in different settings. The WW-FINGERS model can be further developed to integrate pharmacological treatments, as the AD drug development field advances and succeeds in identifying effective disease-modifying compounds. Multidomain schemes combining pharmacological and non-pharmacological interventions can be developed and tested to define secondary and tertiary preventive strategies across the full spectrum of AD.
The WW-FINGERS network facilitates international collaboration in dementia prevention and provides an opportunity to harmonize prevention studies, as well as share experiences and data to obtain maximum scientific impact. Furthermore, the network aims at generating high-quality scientific evidence to support public health and clinical decision-making. This global joint effort can also have a key role in promoting rapid and effective dissemination and implementation of research findings.

 

Funding: This work was supported by the Academy of Finland grants (278457, 287490, 305810, 317465, 319318); Joint Program of Neurodegenerative Disorders – prevention (MIND-AD) grant through the following funding organisations under the aegis of JPND – www.jpnd.eu: Finland, Suomen Akatemia (Academy of Finland, 291803); Sweden, Vetenskapsrådet (VR) (Swedish Research Council, 529-2014-7503); Swedish Research Council grant 2017-06105; Juho Vainio Foundation, Finnish Medical Foundation; Finnish Social Insurance Institution; Ministry of Education and Culture Research Grant; Finnish Cultural Foundation North Savo regional fund, Finnish Brain Foundation; Knut and Alice Wallenberg Foundation Sweden; Center for Innovative Medicine (CIMED) at Karolinska Institutet Sweden; Stiftelsen Stockholms sjukhem Sweden; Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse Sweden; af Jochnick Foundation Sweden; the European Research Council Starting Grant (ERC-804371), Alzheimer Fonden Sweden. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.
Conflict of interest: The authors have no conflicts of interest to declare.

Ethical standards: All studies presented in this article are conducted according to the principles of the Declaration of Helsinki and following the guidelines for Good Clinical Practice. Studies are approved by local ethics committees and all participants provided written informed consent.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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